Summary Combination of Ipilimumab and Nivolumab has emerged as the most effective cancer immunotherapy, resulting in 70% of metastatic melanoma patients to achieve survival beyond three years. However, greater than 50% of the patients developed grades 3-4 immune related adverse events (irAE). In neo-adjuvant setting, the grades 3-4 irAE can reach 73-90%. By increasing the activity of the immune system, combination of Ipilimumab and Nivolumab enhances the host response to inflammatory signals. Although any organ system can be affected, irAEs most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system and cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved. It has been recognized that IrAE is a major bottleneck in cancer immunotherapy: irAEs not only are major threats to patient survival and wellbeing, but also limit the dosing amount and schedule thus reduce the efficacy of cancer immunotherapy. Therefore, novel approach is urgently needed to combat irAE. No prospective trials have defined strategies for effectively managing specific irAEs and the clinical practice remains variable. Here we propose that prevention of irAEs is the best management approach. Danger-associated molecular patterns (DAMPs) are released when tumor cells killed by the host immune system. Accumulating data suggested that innate responses to DAMPs may lead to immune-mediated destruction to host tissues. Since CD24-Siglec G/10 interaction has been shown to dampen response to DAMPs, we hypothesize that fostering activation of Siglec 10 by CD24Fc may reduce irAE among patients receiving Ipilimumab and Nivolumab combination therapy. In support of this hypothesis, we have established a mouse model that fully recapitulate human irAE. We have further demonstrated that CD24Fc effectively reduce severe irAE while enhancing immunotherapeutic effect of Ipilimumab+anti-mouse PD-1. Based on these exciting data, we proposed a phase II clinical trial called CINDI (Combine CD24Fc to Ipilimumab and Nivolumab to Decrease irAE). Since we have obtained proof-of-concept data both for the fundamental concept and for biological activity of CD24Fc in human diseases, we proposed a fast track phase I/II SBIR grant to clinically test our novel hypothesis. Phase I SBIR will achieve the goal to submit IND application and to establish infrastructure required for the CINDI trial. Phase II SBIR will use a fixed dose of CD24Fc to explore the safety and efficacy of combining CD24Fc with ipilimumab and nivolumab to reduce the toxicity of this combination without affecting cancer immunotherapy effects. Our proposed studies represent a new paradigm for prophylaxis of irAE and thus has the potential to greatly improve the horizon of combination immunotherapy.